Diabetes impairs the micro- and macrocirculation, leading to limb ischemia and chronic non-healing wounds. Conventional methods of treating diabetes, such as insulin and oral hypoglycemic agents, can control the disease but do not prevent diabetic complications. This highlights the need for new approaches to therapy. Over the past decade, we defined many of the molecular and cellular perturbations that underlie impaired diabetic wound healing, including defects in both the wound microenvironment and progenitor cell function that contribute to the pathogenesis of diabetic complications. To understand the effects of diabetes on progenitor cell populations with more clarity, we have also developed novel transgenic murine models and single cell gene expression analyses. In this proposal, we will define the discrete defects in progenitor subpopulations are impacted by diabetes and determine whether they are reversible. We will extend this work therapeutically by using cell-based approaches to normalize these defects to treat or reverse diabetic complications including wound healing. To do this, we will utilize lineage tracing and single-cell transcriptional analysis to define the effect of diabetes on progenitor cell subsets and heterogeneity (Specific Aim 1). We will then determine whether diabetes-induced defects in stem/progenitor cell pools are reversible (Specific Aim 2), which will clarify the potential of diabetic cells as a source for cell therapies. Finally, we will use this experimental information t reverse diabetes-induced defects in stem/progenitor cell populations and treat diabetic complications (Specific Aim 3). Taken together, our approach of identifying subpopulation deficits in diabetes and treating these dysfunctions with enriched progenitor subsets will permit highly specific and effective cellular therapy, a much needed alternative to existing treatments for diabetic complications.